File Download

There are no files associated with this item.

  Links for fulltext
     (May Require Subscription)
Supplementary

Article: Requirement of Ras/MAPK pathway activation by transforming growth factor β for transforming growth factor β1 production in a Smad-dependent pathway

TitleRequirement of Ras/MAPK pathway activation by transforming growth factor β for transforming growth factor β1 production in a Smad-dependent pathway
Authors
Issue Date2000
PublisherAmerican Society for Biochemistry and Molecular Biology, Inc. The Journal's web site is located at http://www.jbc.org/
Citation
Journal Of Biological Chemistry, 2000, v. 275 n. 40, p. 30765-30773 How to Cite?
AbstractOur previous results have shown that transforming growth factor β (TGFβ) rapidly activates Ras, as well as both ERKs and SAPKs. In order to address the biological significance of the activation of these pathways by TGFβ, here we examined the role of the Ras/MAPK pathways and the Smads in TGFβ3 induction of TGFβ1 expression in untransformed lung and intestinal epithelial cells. Expression of either a dominant-negative mutant of Ras (RasN17) or a dominant-negative mutant of MKK4 (DN MKK4), or addition of the MEK1 inhibitor PD98059, inhibited the ability of TGFβ3 to induce AP-1 complex formation at the TGFβ1 promoter, and the subsequent induction of TGFβ1 mRNA. The primary components present in this TGFβ3-inducible AP-1 complex at the TGFβ1 promoter were JunD and Fra-2, although c-Jun and FosB were also involved. Furthermore, deletion of the AP-1 site in the TGFβ1 promoter or addition of PD98059 inhibited the ability of TGFβ3 to stimulate TGFβ1 promoter activity. Collectively, our data demonstrate that TGFβ3 induction of TGFβ1 is mediated through a signaling cascade consisting of Ras, the MAPKKs MKK4 and MEK1, the MAPKs SAPKs and ERKs, and the specific AP-1 proteins Fra-2 and JunD. Although Smad3 and Smad4 were not detectable in TGFβ3-inducible AP-1 complexes at the TGFβ1 promoter, stable expression of dominant-negative Smad3 could significantly inhibit the ability of TGFβ3 to stimulate TGFβ1 promoter activity. Transient expression of dominant-negative Smad4 also inhibited the ability of TGFβ3 to transactivate the TGFβ1 promoter. Thus, although the Ras/MAPK pathways are essential for TGFβ3 induction of TGFβ1, Smads may only contribute to this biological response in an indirect manner.
Persistent Identifierhttp://hdl.handle.net/10722/171684
ISSN
2015 Impact Factor: 4.258
2015 SCImago Journal Rankings: 3.151
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorYue, Jen_US
dc.contributor.authorMulder, KMen_US
dc.date.accessioned2012-10-30T06:16:20Z-
dc.date.available2012-10-30T06:16:20Z-
dc.date.issued2000en_US
dc.identifier.citationJournal Of Biological Chemistry, 2000, v. 275 n. 40, p. 30765-30773en_US
dc.identifier.issn0021-9258en_US
dc.identifier.urihttp://hdl.handle.net/10722/171684-
dc.description.abstractOur previous results have shown that transforming growth factor β (TGFβ) rapidly activates Ras, as well as both ERKs and SAPKs. In order to address the biological significance of the activation of these pathways by TGFβ, here we examined the role of the Ras/MAPK pathways and the Smads in TGFβ3 induction of TGFβ1 expression in untransformed lung and intestinal epithelial cells. Expression of either a dominant-negative mutant of Ras (RasN17) or a dominant-negative mutant of MKK4 (DN MKK4), or addition of the MEK1 inhibitor PD98059, inhibited the ability of TGFβ3 to induce AP-1 complex formation at the TGFβ1 promoter, and the subsequent induction of TGFβ1 mRNA. The primary components present in this TGFβ3-inducible AP-1 complex at the TGFβ1 promoter were JunD and Fra-2, although c-Jun and FosB were also involved. Furthermore, deletion of the AP-1 site in the TGFβ1 promoter or addition of PD98059 inhibited the ability of TGFβ3 to stimulate TGFβ1 promoter activity. Collectively, our data demonstrate that TGFβ3 induction of TGFβ1 is mediated through a signaling cascade consisting of Ras, the MAPKKs MKK4 and MEK1, the MAPKs SAPKs and ERKs, and the specific AP-1 proteins Fra-2 and JunD. Although Smad3 and Smad4 were not detectable in TGFβ3-inducible AP-1 complexes at the TGFβ1 promoter, stable expression of dominant-negative Smad3 could significantly inhibit the ability of TGFβ3 to stimulate TGFβ1 promoter activity. Transient expression of dominant-negative Smad4 also inhibited the ability of TGFβ3 to transactivate the TGFβ1 promoter. Thus, although the Ras/MAPK pathways are essential for TGFβ3 induction of TGFβ1, Smads may only contribute to this biological response in an indirect manner.en_US
dc.languageengen_US
dc.publisherAmerican Society for Biochemistry and Molecular Biology, Inc. The Journal's web site is located at http://www.jbc.org/en_US
dc.relation.ispartofJournal of Biological Chemistryen_US
dc.subject.meshAnimalsen_US
dc.subject.meshBacterial Proteins - Metabolismen_US
dc.subject.meshBase Sequenceen_US
dc.subject.meshCell Lineen_US
dc.subject.meshCulture Media, Serum-Freeen_US
dc.subject.meshDna-Binding Proteins - Metabolismen_US
dc.subject.meshEnzyme Activationen_US
dc.subject.meshEnzyme Inhibitors - Pharmacologyen_US
dc.subject.meshEpithelial Cells - Metabolismen_US
dc.subject.meshFlavonoids - Pharmacologyen_US
dc.subject.meshFos-Related Antigen-2en_US
dc.subject.meshGenes, Dominanten_US
dc.subject.meshGenes, Ras - Geneticsen_US
dc.subject.meshIntestines - Metabolismen_US
dc.subject.meshKineticsen_US
dc.subject.meshLiver - Metabolismen_US
dc.subject.meshLuciferases - Metabolismen_US
dc.subject.meshLung - Metabolismen_US
dc.subject.meshMap Kinase Kinase 4en_US
dc.subject.meshMap Kinase Signaling Systemen_US
dc.subject.meshMinken_US
dc.subject.meshMitogen-Activated Protein Kinase Kinases - Geneticsen_US
dc.subject.meshMolecular Sequence Dataen_US
dc.subject.meshMutagenesis, Site-Directeden_US
dc.subject.meshPlasmids - Metabolismen_US
dc.subject.meshPromoter Regions, Geneticen_US
dc.subject.meshProtein Bindingen_US
dc.subject.meshProto-Oncogene Proteins C-Fosen_US
dc.subject.meshProto-Oncogene Proteins C-Jun - Metabolismen_US
dc.subject.meshRna, Messenger - Metabolismen_US
dc.subject.meshRatsen_US
dc.subject.meshRibonucleases - Metabolismen_US
dc.subject.meshSignal Transductionen_US
dc.subject.meshSmad3 Proteinen_US
dc.subject.meshSmad4 Proteinen_US
dc.subject.meshTime Factorsen_US
dc.subject.meshTrans-Activators - Metabolismen_US
dc.subject.meshTranscription Factor Ap-1 - Metabolismen_US
dc.subject.meshTranscription Factors - Metabolismen_US
dc.subject.meshTransfectionen_US
dc.subject.meshTransforming Growth Factor Beta - Biosynthesis - Metabolismen_US
dc.subject.meshTransforming Growth Factor Beta1en_US
dc.subject.meshTransforming Growth Factor Beta3en_US
dc.subject.meshRas Proteins - Physiologyen_US
dc.titleRequirement of Ras/MAPK pathway activation by transforming growth factor β for transforming growth factor β1 production in a Smad-dependent pathwayen_US
dc.typeArticleen_US
dc.identifier.emailYue, J:jyue@hku.hken_US
dc.identifier.authorityYue, J=rp00286en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1074/jbc.M000039200-
dc.identifier.pmid10843986-
dc.identifier.scopuseid_2-s2.0-0034613385en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-0034613385&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume275en_US
dc.identifier.issue40en_US
dc.identifier.spage30765en_US
dc.identifier.epage30773en_US
dc.identifier.isiWOS:000089762700006-
dc.publisher.placeUnited Statesen_US
dc.identifier.scopusauthoridYue, J=7101875828en_US
dc.identifier.scopusauthoridMulder, KM=7005187184en_US

Export via OAI-PMH Interface in XML Formats


OR


Export to Other Non-XML Formats